Prsentation PowerPoint

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MICROSATELLITE INSTABILITY AND CANCERS MAI 2006
Alex Duval INSERM U762 Fondation Jean Dausset -
CEPH 27, rue Juliette Dodu 75010 Paris
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MICROSATELLITE INSTABILITY AND CANCERS -
COMPOSITION OF THE UNIT Alex DUVAL I.
Genetics of MSI cancers Richard
HAMELIN Martine MULERIS Marc
POCARD Françoise PRAZ II. Study and
relationship between immunity and MSI
carcinogenesis Alex DUVAL Jean-François
FLEJOU III. MSI cancers from biology to
clinic
STUDENTS ITA Alexandra CHALASTANIS
M2 Olivier BUHARD AI INSERM Emilie CAPEL
Marie-Annick MARRY TR INSERM Ann-Sophie
SCHREURS Evelyne THAI VAC INSERM Jé
rome VIGUIER DOCTORANTS Alexandre AIME Magali
SVRCEK Peggy CUILLIERE Claire BORIE Jamila
EL BCHIRI
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TCCAAAAAAAAAAAAAAAAAAAAAGTC
TCCAAAAAAAAAAAAAAAAAGTC
TCCAAAAAAAAAAAAAAAGTC
TCCAAAAAAAAAAAGTC
GCTTCACACACACACACACACACACACACATCC
GCTTCACACACACACACACACACACATCC
GCTTCACACACACACACACATCC GCTTCACACACACACACATCC GC
TTCACACACACACATCC
Aaltonen et al., Science, 1993
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THE CLINICAL SPECTRUM OF MSI CANCERS
HEREDITARY HNPCC (LYNCH SYNDROME) EARLY
OCCURING
SPORADIC CASES LATE OCCURING
COLON STOMACH ENDOMETRIUM
CONSTITUTIONAL MMR GENE MUTATION (ponctual
alteration of hMLH1, hMSH2 ... )
SOMATIC MMR GENE ALTERATION (promotor
methylation of hMLH1, ... )
ovary, pancreas, small bowel, kydney, brain, ...
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Genetic Instability in Human Cancers

• ONCOGENIC PATHWAYS
• IN MSI CANCERS?
• MSI
• 2. CHROMOSOMAL INSTABILITY
• 3. EPIGENETIC CHANGES
• (METHYLATION)

LOH
MSI
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THE MUTATOR PATHWAY IN MSI CANCERS
PROTEIN
mRNA
STOP
AAAAAAAAAA
ATG
5 UTR
3 UTR
TARGET GENE FOR MSI
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PROTeiin
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SIGNALING
TGFßRII IGFIIR PTEN AXIN2 TCF4 GRB14 RIZ
DNA REPAIR
BLM RAD50 BRCA2 MSH3 MSH6 MBD4 DNA-PKcs ATR
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STOP
ATG
AAAAAAAAAA
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MSI
TGFßRII, BAX, IGFIIR, ...
MLH1, MSH2
ABERRANT CRYPT
ADENOMA
COLORECTAL CANCER
LOH
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Parc et al, Gut 2004
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MICROSATELLITE INSTABILITY AND CANCERS - THE
RESEARCH PROJECT

• I. GENETICS OF MSI CANCERS
• II. STUDY OF THE RELATIONSHIP BETWEEN IMMUNITY
  AND MSI CARCINOGENESIS
• III. MSI CANCERS FROM BIOLOGY TO CLINIC

• Towards the construction and the exploitation of
  biological ressources specific for these tumors
• Cytogenetics of MSI tumors
• The response of MSI cancers to chemotherapeutic
  drugs functional analysis
• Genetic study of the metastatic process of
  colorectal MSI tumors using the model of
  xenografts
• in nude mice

• Study of the occurrence and analysis of the MSI
  phenotype in immunodeficiency-related tumors
• Inhibiting Nonsense Mediated Decay in MSI cancers

• Clinical exploitation of biological ressources
  specific of MSI cancers
• Alternative therapeutic strategies in MSI
  colorectal cancers

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CGH AND EXPRESSION ARRAY PROFILING ON PRIMARY
COLORECTAL CANCERS
LOH (Strasbourg) N 60
MSI (Paris) N 50
NONLOH - NONMSI (Paris) N 20
Projet LNCC/Inca/INSERM
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• Methodology
• LOH and MSI status of tumour samples have been
  determined
• Tumour DNAs and RNAs have been extracted and
  quantified
• Collect of Clinical data are in Progress
• Aims of the study
• Basic but also Clinical
• Concerns all Colorectal tumour subtypes (LOH,
  MSI, CIMP, )

Projet LNCC/Inca/INSERM
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ROLE OF IMMUNOSUPPRESSION ?
CD3
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TOTAL
NON ID
ID
HIV cases
PTLD cases
B CELL NHL DLBCL 248 117 60 75
BL 93 43 46 4 PCNSL 13 0 8 5
P-PTLD 19 0 0 19 P-PTLD LIKE 6 0 6 0 HL-
LIKE 2 0 0 2 OTHER 178 177 1 0 TOTAL
(B-NHL) 559 337 121 102 T CELL NHL PTCL
31 23 1 7 AILD 4 4 0 0 ALCL 3 0 3
0 TOTAL (T-NHL) 38 27 4 7 UNKNOWN 6 0 3 2
TOTAL 603 364 128 111
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Towards the characterization of a new subtype of
human lymphomas
NHL - PT - MSI
NHL subtype
Sex
Age
Organ transplanted
Tumoral Localization
Immunosupressive regimen
Clonality
EBV Status
Survey
NHL - HIV- MSI
CD4
HAART
Proc. Nat. Acad Sci., 2004
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CLINICAL FEATURES OF MSI LYMPHOMAS

• Rare in the General Population (2 of the NHL in
  human)
• But frequent in immunodeficient patients (10 of
  the NHL occuring after graft, 3
• of the NHL occuring in patients suffering from
  AIDS)
• MSI Lymphomas are T-Cell Lymphomas 25 of
  T-NHL are MSI
• in immunodeficient patients
• No Gender difference, as compared to other MSI
  cancers
• Late occuring after graft (109 months)

Other MSI cancers occur in the context of
Immunodeficiency ???
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• increased risk of CRC in patients with ulcerative
  colitis (UC) and Crohns disease (CD)
• increased risk of small intestinal adenocarcinoma
  in CD

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• MSI
• 10/70 CRCs (14) (6 patients 2 CD and 4 UC)
• 0/6 small intestinal adenocarcinomas (0)

prevalence of MSI IBD-associated cancers 13
NR-21
BAT-26
MSS
MSI
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• IHC
• loss of expression of one MMR protein in all 10
  MSI CRC complicating IBD

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THE NONSENSE MEDIATED mRNA DECAY SYSTEM
EJC (Exon-Junction Complex)
RNPS1 Aly/REF Y14 SRm160 UAP56
hUpf1
1
hUpf2
hUpf3
(From Holbrook et al., Nature Genet. 2004)
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Hum Mol Genet., 2005
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Negative control (scrambled siRNA)
CO115 (MMR deficient )
NMD silencing
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In Vivo silencing of NMD in nude mice grafted
with HCT116
control
treated
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Leads to a significant decrease of HCT116
growth in 15 days
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Gastroenterology 2002
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East Asia (319/19)
Europe (161/8)
Italy 50/3
France 53/2
Caucasus 17/1
Siberia 25/1
Orkney Island 16/1
Russia 25/1
Middle East/ North Africa (278/6)
China 184/15
Hong-Kong 68/1
Japan 31/1
Israël 148/3
1
Cambodia 11/1
100/2
Algeria 30/1
2
Central Asia (200/8)
America (108/5)
Pakistan 200/8
Mexico 50/2
Bougainville 22/1
Colombia 13/1
NewGuinea 17/1
Central African Rep. 36/1
Kenya 12/1
Senegal 24/1
Congo 15/1
Africa (127/7)
Oceania (39/2)
Brazil 45/2
South Africa 8/1
Namibia 7/1
Nigeria 25/1
Buhard et al., JCO 2006
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MICROSATELLITE INSTABILITY AND CANCERS -
COMPOSITION OF THE UNIT Alex DUVAL I.
Genetics of MSI cancers Richard
HAMELIN Martine MULERIS Marc
POCARD Françoise PRAZ II. Study and
relationship between immunity and MSI
carcinogenesis Alex DUVAL Jean-François
FLEJOU III. MSI cancers from biology to
clinic
STUDENTS ITA Alexandra CHALASTANIS
M2 Olivier BUHARD AI INSERM Emilie CAPEL
Marie-Annick MARRY TR INSERM Ann-Sophie
SCHREURS Evelyne THAI VAC INSERM Jé
rome VIGUIER DOCTORANTS Alexandre AIME Magali
SVRCEK Peggy CUILLIERE Claire BORIE Jamila
EL BCHIRI